1. Technical Field
The present invention relates, in general, to compounds that inhibit protein kinase activity, and to compositions and methods related thereto.
2. Description of the Related Art
Cancer (and other hyperproliferative diseases) is characterized by uncontrolled cell proliferation. This loss of the normal control of cell proliferation often appears to occur as the result of genetic damage to cell pathways that control progress through the cell cycle. The cell cycle consists of DNA synthesis (S phase), cell division or mitosis (M phase), and non-synthetic periods referred to as gap 1 (G1) and gap 2 (G2). The M-phase is composed of mitosis and cytokinesis (separation into two cells). All steps in the cell cycle are controlled by an orderly cascade of protein phosphorylation and several families of protein kinases are involved in carrying out these phosphorylation steps. In addition, the activity of many protein kinases increases in human tumors compared to normal tissue and this increased activity can be due to many factors, including increased levels of a kinase or changes in expression of co-activators or inhibitory proteins.
Cells have proteins that govern the transition from one phase of the cell cycle to another. For example, the cyclins are a family of proteins whose concentrations increase and decrease throughout the cell cycle. The cyclins turn on, at the appropriate time, different cyclin-dependent protein kinases (CDKs) that phosphorylate substrates essential for progression through the cell cycle. Activity of specific CDKs at specific times is essential for both initiation and coordinated progress through the cell cycle. For example, CDK1 is the most prominent cell cycle regulator that orchestrates M-phase activities. However, a number of other mitotic protein kinases that participate in M-phase have been identified, which include members of the polo, aurora, and NIMA (Never-In-Mitosis-A) families and kinases implicated in mitotic checkpoints, mitotic exit, and cytokinesis.
Axl is a receptor tyrosine kinase (ligand: Growth Arrest Specific protein 6, Gas6) which is unique in having two tandem immunoglobulin-like repeats and two fibronectin type III repeats, a feature common in cellular adhesion molecules. For this reason, it has a family of its own, the Axl/Ufo subfamily of tyrosine kinases. The expression of Axl/Gas6 has been shown in a number of human malignancies, including ovarian, melanoma, renal cell carcinoma, uterine leiomyoma, uterine endometrial cancer, thyroid carcinoma, gastric cancer, breast cancer, NSCLC, CML, AML, colorectal carcinoma, prostate cancer, various lymphomas, and esophageal cancer. The Axl protooncogene is thus an attractive and valuable target for the discovery and development of new therapeutic agents.
Based on the involvement in a number of human malignancies, there is a need for the design of specific and selective inhibitors for the treatment of cancer and other conditions mediated and/or associated with Axl kinase. The present invention fulfills these needs and offers other related advantages.